The present invention is generally directed to cancer prevention, treatment and therapy, and more particularly to in vivo methods for treating pancreatic cancer using a purified fraction of crude crocetin, including crocetinic acid.
Cancer is a major public health problem in the United States and many other parts of the world. Currently, one in four deaths in the United States is due to cancer. Pancreatic cancer is the fourth leading cause of cancer deaths in developing countries and worldwide and about more than 250,000 cases are diagnosed annually.
There is a significant increase in cancer deaths due to pancreatic cancer (31,000 deaths in 2007 to approximately 37,460 deaths in 2012) in the United States in recent days and there is no significant treatment available at present for pancreatic cancer (Reference 1). There are reports on the use of saffron to treat various diseases, particularly cancer, by the ancient Indian, Egyptian, and Chinese cultures. Saffron is present in the dry stigmas of the plant Crocus sativus L., and is used as a spice and a food colorant (References 2-6). Crocetin is a carotenoid extract from the stigma of saffron flower (Crocus sativus) and is an amphiphilic terpenoid. By structural analysis, it is a C-18 polyunsaturated carbon chain with COOH group at each end. It is used as anticancer drug in folklore Chinese, Indian, and Egyptian herbal medicine. It is reported to inhibit intracellular nucleic acid and protein synthesis (References 6-7). Experimental study on rat and human colon adenocarcinoma cells, pancreatic and breast cancer cells demonstrated promising effects on cancer (Reference 8). Crocetin inhibits pancreatic cancer cell proliferation and tumor progression in a xenograft mouse model. Comprehensive chemical analysis of saffron extract has demonstrated that major constituents include carotenoids, and in particular, crocetin (References 7-8).
It has been demonstrated that commercial or crude crocetin inhibited in vitro pancreatic cancer cell proliferation and tumor progression in a xenograft mouse model (References 7-8). It was reported first in 1990s and confirmed in recent years that saffron extract inhibited growth of malignant cells in vitro and also in vivo (References 9-11). Inhibition of DNA, RNA and protein synthesis was demonstrated in three human malignant cells exposed to crocetin (Reference 12) and the mechanism of action was reported through suppression of the activity of DNA-dependent RNA polymerase II (References 13-14).
Another study also demonstrated that crocetin reduces in vitro histone H1-DNA interaction and interfered with transcription (Reference 15). Crocetin and carotenoids in general, showed cytotoxic effects on a range of tumors and malignant cells (Reference 8).
During the last decade, a number of studies in animal model systems have demonstrated an antitumor effect of saffron (Reference 8). One in vivo study reported that crocetin has antitumor activity in a lung cancer animal model by scavenging free radicals and drug metabolizing enzymes (Reference 16). In a recent in vitro study, crocetin demonstrated significant reduction of cell proliferation in both MCF-7 and MDA-MD-231 breast cancer cells (Reference 17).
Collectively, these studies provide strong evidence of the antitumor activity of crocetin. Given the potential importance of crocetin, this series of experiments was designed to examine the effect of crocetin on pancreatic adenocarcinoma cells and also to evaluate whether it has an antitumorigenic effect on pancreatic cancer in an athymic (nude) mice model.